Combination Therapy for Advanced Breast Cancer

Recruiting at 2 trial locations

Overseen By Polly A Niravath, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: The Methodist Hospital Research Institute

Must not be taking: Warfarin, Strong CYP3A4 inhibitors

Disqualifiers: HIV, Hypertension, Cardiac abnormalities, Diabetes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 6

Duration: 18 weeks

36 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of an oral cancer drug, an IV chemotherapy drug, and another IV drug in patients with a rare, hard-to-treat type of breast cancer. The goal is to improve treatment response by blocking cancer growth signals and resistance pathways. The study targets patients whose cancer has not responded to other treatments.

Will I have to stop taking my current medications?

The trial requires that you stop taking strong inhibitors or inducers of CYP3A4 at least 1 week before starting the study. If you are on warfarin or other coumarin-derived anticoagulants, you will need to switch to a different type of blood thinner. Other medications that interact with nitrate/nitrite levels are also not allowed.

What makes the drug L-NMMA unique for treating advanced breast cancer?

L-NMMA is unique because it works by inhibiting nitric oxide synthase, an enzyme that produces nitric oxide, which can promote tumor growth and blood vessel formation in cancers. This mechanism is different from many standard breast cancer treatments that typically target hormone receptors or specific cancer cell proteins. ^{1 2 3 4 5}

Who Is on the Research Team?

Polly Niravath, MD

Principal Investigator

Houston Methodist Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with HER2 negative metastatic or advanced metaplastic breast cancer that hasn't improved after previous treatments. Participants must be able to follow the study plan, have measurable disease, and acceptable organ function. Women of childbearing age and sexually active men must use contraception. Exclusions include certain drug interactions, uncontrolled hypertension, serious heart conditions, other active cancers, severe lung disease or neuropathy, pancreatitis, blood clotting disorders on specific anticoagulants, history of severe skin reactions or untreated brain metastases.

Inclusion Criteria

My breast cancer is HER2 negative with specific cell types.

I have fully recovered from any major surgery before starting the study treatment.

Willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations

Exclusion Criteria

Pregnant, breastfeeding or expecting to conceive children within the projected duration of the study, starting with the prescreening or screening visit through 30 days after the last dose of study treatment

I do not have severe lung disease or lung scarring.

Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive alpelisib, L-NMMA, and nab-paclitaxel every 3 weeks until disease progression, toxicity, or withdrawal

18 weeks

6 cycles (in-person visits every 3 weeks)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• L-NMMA

Trial Overview The study tests the combination of alpelisib (taken orally), L-NMMA (given intravenously), and nab-paclitaxel chemotherapy in patients with a specific type of breast cancer. Treatments are given every three weeks until disease progression or unacceptable side effects occur.

How Is the Trial Designed?

Group I: iNOS inhibitor and nab-paclitaxel in combination with alpelisib. Experimental Treatment 1 Intervention

iNOS inhibitor and nab-paclitaxel in combination with alpelisib in patients with HER2 negative, metastatic or locally advanced MpBC.

Who Is Running the Clinical Trial?

The Methodist Hospital Research Institute

Lead Sponsor

Trials

299

Recruited

82,500+

Novartis Pharmaceuticals

Industry Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

In a study of 168 patients undergoing 177Lu-PSMA therapy for metastatic castration-resistant prostate cancer, a higher PD-L2 signature was linked to significantly longer overall survival (OS), suggesting it may enhance treatment response.

Conversely, PD-L1 levels did not show a significant association with patient outcomes, indicating that PD-L2 may be a more relevant biomarker for predicting the efficacy of 177Lu-PSMA therapy, particularly in patients with lower LDH levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysing the tumor transcriptome of prostate cancer to predict efficacy of Lu-PSMA therapy. Handke, A., Kesch, C., Fendler, WP., et al.[2023]

In a phase II clinical trial involving 44 prostate cancer patients, the addition of GM-CSF to DC-peptide infusions did not significantly enhance clinical responses, with only 1 complete and 8 partial responders compared to 2 complete and 17 partial responders in the control group.

While GM-CSF was associated with some mild side effects like local injection reactions and fatigue, it did not lead to a detectable improvement in immune responses when compared to patients who did not receive GM-CSF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GM-CSF as a systemic adjuvant in a phase II prostate cancer vaccine trial. Simmons, SJ., Tjoa, BA., Rogers, M., et al.[2022]

PSMA cleaves specific peptides from the extracellular matrix protein laminin, which are crucial for activating endothelial cells and promoting angiogenesis, particularly in the context of prostate cancer.

The study identified LQE as a substrate for PSMA, and its cleavage product LQ was shown to enhance angiogenesis in vivo, suggesting that targeting PSMA could be a potential strategy for developing new cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prostate-specific membrane antigen (PSMA)-mediated laminin proteolysis generates a pro-angiogenic peptide. Conway, RE., Rojas, C., Alt, J., et al.[2018]

In a mouse model of prostate cancer, combining PSMA-targeted radionuclide therapy (RNT) with anti-PD-1 immunotherapy significantly improved tumor control and survival compared to either treatment alone, with time to progression extending to 47.5 days and survival to 51.5 days.

Both PSMA RNT and anti-PD-1 alone showed some efficacy in prolonging time to progression and survival, but the combination therapy demonstrated a synergistic effect, highlighting the potential for combined treatment strategies in prostate cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune-Checkpoint Blockade Enhances 225Ac-PSMA617 Efficacy in a Mouse Model of Prostate Cancer. Czernin, J., Current, K., Mona, CE., et al.[2023]

In a study of 33 patients with metastatic castration-resistant prostate cancer undergoing [177Lu]-PSMA-617 therapy, baseline tumor volume (PSMA-TV) was found to be a significant predictor of overall survival (OS), indicating that larger tumor volumes at the start of treatment correlate with poorer outcomes.

Reduction in PSMA-TV after two therapy cycles did not generally predict better OS for the entire cohort; however, in patients with higher PSMA expression, a reduction in PSMA-TV was associated with improved survival, suggesting that PSMA expression levels may influence the effectiveness of tumor volume assessments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Total tumor volume reduction and low PSMA expression in patients receiving Lu-PSMA therapy. Seifert, R., Kessel, K., Schlack, K., et al.[2022]

Citations

1. England pubmed.ncbi.nlm.nih.gov

Analysing the tumor transcriptome of prostate cancer to predict efficacy of Lu-PSMA therapy. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

GM-CSF as a systemic adjuvant in a phase II prostate cancer vaccine trial. [2022]

3. Germany pubmed.ncbi.nlm.nih.gov

Prostate-specific membrane antigen (PSMA)-mediated laminin proteolysis generates a pro-angiogenic peptide. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Immune-Checkpoint Blockade Enhances 225Ac-PSMA617 Efficacy in a Mouse Model of Prostate Cancer. [2023]

5. Australia pubmed.ncbi.nlm.nih.gov

Total tumor volume reduction and low PSMA expression in patients receiving Lu-PSMA therapy. [2022]